Jessica L. Giordano

Objective: Expert prenatal focused gene‐disease curation is necessary to accurately inform clinical care in the setting of rapidly expanding prenatal genomic sequencing. Methods: An international Prenatal Gene Curation Expert Panel assembled and systematically reviewed genes asserted to be associated with prenatal hydrops, stillbirth, or severe anomalies using the ClinGen framework. Results: The ClinGen Prenatal GCEP published evidence summaries for 63 disease relationships involving 61 genes with unique and clinically severe prenatally observed fetal phenotypes. Conclusion: The ClinGen Prenatal GCEP work addresses a gap in genomic medicine by deepening our understanding of lethal and severe prenatal phenotypes, while supporting accurate diagnosis, counseling, and future treatment strategies in prenatal care.

Stillbirth affects approximately 1 in 175 pregnancies annually in the United States. Although the American College of Obstetricians and Gynecologists recommends genetic testing as part of the stillbirth evaluation, families often face barriers to obtaining a complete evaluation. Expansion of the diagnostic evaluation of stillbirth is expected to include exome/genome sequencing, with preliminary studies demonstrating its diagnostic utility. Consequently, genetic counselors (GCs) are expected to play an expanding role in post‐stillbirth care. This study explored current genetic counseling practices for stillbirth and GCs' preparedness to support patients in this setting. A cross‐sectional survey was distributed across four channels. Eligible participants included GCs in the United States and Canada with at least 1 year of prenatal experience. The survey assessed GC frequency and timing in stillbirth counseling, genetic testing practices, comfort addressing psychosocial needs, and perceived barriers to care. Responses were analyzed using descriptive statistics. Group comparisons were performed using Chi‐square and Fisher's exact tests. Open‐ended responses were coded for themes. Seventy‐one responses were analyzed. Approximately half of respondents (49.3%, n = 36) reported “never/very rarely/rarely” counseling patients postpartum, despite this being the optimal time to offer genetic testing. Delivering providers (46.5%, n = 33) were often responsible for informing patients about testing and obtaining consent, compared to GCs (11.3%, n = 8). Although chromosomal microarray (CMA) is recommended as the standard of care (SOC), 12.7% ( n = 9) of GCs reported not offering CMA for anomalous and non‐anomalous stillbirths. Perceived barriers to SOC testing included reported lack of obstetrician awareness (91.5%, n = 65) and challenges coordinating specimen collection (90.1%, n = 64). These findings highlight barriers to SOC genetic evaluation and underscore the need to strengthen institutional protocols, enhance provider education, and develop stillbirth‐specific genetic counseling guidelines. GC involvement in these efforts will be essential to promoting equitable access to comprehensive post‐stillbirth care as sequencing becomes integrated into practice.

Prenatal genomic sequencing can detect far more than clinicians conventionally report. Whether adult-onset conditions diagnosed in the fetus should be disclosed prenatally remains debated, and most laboratories and guidelines restrict reporting to childhood-onset disease. We argue that this restriction is not supported by available evidence. Prospective parents consistently elect to receive adult-onset findings, most often to plan for a child’s future health. Pediatric and newborn sequencing studies have not demonstrated the psychological, relational, or developmental harms critics anticipated, and pregnancy offers an unmatched opportunity to reach an otherwise unscreened population. Policy should be guided by informed consent and patient autonomy.

Introduction: Cleft lip and palate (CLP) are common congenital disruptions of the orofacial cleft and are associated with numerous genetic conditions. This study examines prenatal findings, clinical outcomes, and genetic findings among prenatally diagnosed CLP, with a focus on the yield of next‐generation sequencing (NGS). Methods: This was a retrospective cohort study of prenatally diagnosed CLP presenting to a tertiary‐care referral center between 2017 and 2024. Inclusion required pre‐/postnatal diagnostic genetic testing. Imaging findings, genetic diagnoses, and delivery and postnatal outcomes were compared between those with isolated CLP (iCLP) and CLP with additional anomalies (CLP+). t ‐tests, Wilcoxon rank‐sum test, chi‐square test, or Fisher's exact test were used as appropriate. Results: A total of 57 pregnancies met inclusion criteria: 19 (33.3%) iCLP and 38 (66.7%) CLP+. Among CLP+, the most common additional prenatally detected anomalies were central nervous system (55.3%) and cardiac (52.6%). Groups had similar rates of termination and live birth (26.0% and 68.0% overall, respectively). Neonatal intensive care unit (NICU) admission was frequent at 70.6%, and similar between groups (50.0% iCLP vs. 81.8% CLP+, p = 0.11). Across the cohort, 21 (36.8%) pregnancies had reported findings from genetic testing, with 16 (28.1% of total cohort, 76.2% of those with genetic findings) possessing findings explanatory of CLP. CLP+ pregnancies were more likely to have explanatory genetic findings (36.8% vs. 10.5%, p = 0.04). Eleven of 16 (68.8%) likely causative findings were detected via karyotype/CMA. Among 29 patients with NGS, five (17.2%) had likely causative variants not detected by karyotype/CMA. NGS increased overall pathogenic diagnostic yield from 19.3% to 28.1% and diagnosed additional clinically relevant findings in three cases. Conclusion: Postnatal outcomes were overall similar between groups, with high rates of NICU admission. While CLP+ had higher rates of genetic findings, all CLP had risk of genetic disorders. In cases with non‐causative karyotype/CMA, sequencing revealed explanatory diagnostic variants in one in six cases, increasing diagnostic yield by nearly 10%. We advocate for comprehensive prenatal imaging and diagnostic genetic evaluation, including sequencing, for all prenatal CLP cases.

Objective: This study evaluates an understudied perspective: the experiences of prospective parents who decline prenatal genome sequencing (pGS) for continuing pregnancies with fetal structural anomalies. Method: We recruited a total cohort of 300 parents of 150 pregnancies who declined pGS, including 33 individuals who underwent an invasive procedure. These parents were invited to participate in a semi‐structured interview between 1 and 15 months post‐partum. We used Thematic Analysis to code and analyze interviews. Results: We interviewed 22 parents of 16 pregnancies. Reasons for declining testing included risks of invasive procedures ( n = 19, 86%), lack of prenatally actionable findings ( n = 17, 77%), unclear benefits of testing ( n = 9, 41%), satisfaction with previous testing ( n = 11, 50%), expected low diagnostic yield ( n = 13, 59%), emotional and information overload ( n = 11, 50%), intolerance of uncertainty ( n = 13, 59%), and privacy concerns ( n = 5, 23%). Most individuals indicated that, if available, they would elect non‐invasive prenatal sequencing. Overall, participants were satisfied with their choice to decline pGS and had no regrets postnatally. Conclusions: The reasons individuals declined pGS included medical and emotional risks of testing and an understanding of potential results and their utility. To address these concerns, pretest genetic counseling should include the probability of diagnostic results, impact of prenatal/perinatal management, consideration of uncertain results, privacy concerns, and benefits and limitations of postnatal testing. Non‐invasive prenatal sequencing, currently under investigation in research settings, may be an alternative future option, but will not address all concerns. Given that our cohort was small and homogenous, lacked cost burden, excluded terminated pregnancies, and included no postnatal genetic diagnoses, further research is needed to confirm that these findings are generalizable.

Objective: This study aimed to explore participant reflections after receipt of prenatal genome sequencing (GS) results in the absence of fetal anomalies. Methods: Participants invited to complete a semi‐structured interview consented to future research, were English speaking, and were between 30 days and 1 year since the conclusion of their sequenced pregnancy. A total of 18 interviews were conducted with 21 participants (3 couples interviewed concurrently) representing 15 unique pregnancies (81% term deliveries, 14% terminated pregnancies, and 5% preterm delivery). Interviews were transcribed, coded, and analyzed using a constructivist grounded theory approach. Results: Participants had various motivations for pursuing GS, yet all wanted maximal information. Almost all participants with positive results had downstream implications, including termination, cascade testing, referral to specialists, and changes in pregnancy management and neonatal care. Negative results provided reassurance for the pregnancy and child's early development. If available, most participants would pursue GS in a future pregnancy; however, a few raised concerns about cost and accessibility. Conclusion: Understanding the perspectives and needs of pregnant patients and their partners will help inform the implementation of GS as a first‐tier prenatal diagnostic test.

Differentially methylated regions (DMRs) in certain areas of the genome are subject to genomic imprinting. DMRs at chromosome 11p15.5 are associated with Beckwith‐Wiedemann syndrome (BWS) and Russell–Silver Syndrome (RSS), two growth disorders with opposite phenotypes. We identified a maternally inherited duplication containing part of the 11p15 DMR in a non‐anomalous fetus in first trimester using genome sequencing (GS). The ∼281kb duplication at 11p15.5 contains the entire imprinting control region 1 (ICR1) and the H19 gene but lacks the IGF2 gene and the imprinting control region 2 (ICR2). Methylation studies revealed hypomethylation of ICR1 in fetal cells as well as in the mother (leukocytes), who had a history of feeding difficulties in infancy and short stature. The duplication was inherited from the asymptomatic maternal grandmother of the fetus, who showed hypermethylation of ICR1 in leukocytes suggesting paternal inheritance. The fetus developed decelerating growth in late gestation and phenotypes overlapping those of RSS were noted in infancy. This study adds to the limited literature on partial duplications of the 11p15.5 region and their associated phenotypes, underscoring the efficacy of GS in cases involving DMRs associated with imprinting disorders.

Background: Chondrodysplasia punctata 1 (CDPX1) is an X‐linked recessive disorder of cartilage and bone development characterized by stippling on the cartilage and bone, flattened nasal bridge, and brachydactyly, or short fingers. CDPX1 has been associated with variants in the ARSL gene and is known to manifest prenatally, however, there has been no systematic literature review on this evidence.Aims: Here, we reviewed the current literature on prenatal manifestations of CDPX1, and additionally introduce previously unpublished cases.Materials & Methods: A systematic review of the literature was performed. Additionally, a GeneMatcher submission was created and a call for cases was presented at the Fetal Sequencing Consortium meetings to find previously unpublished cases.Results: For the 22 fetuses reported here, we found that 55% had nasal hypoplasia, 41% had bony stippling or calcifications, 32% had polyhydramnios, 5% had oligohydramnios, 23% had shortened long bones, 23% had spinal canal stenosis, 18% had ventriculomegaly, 9% had brachydactyly/brachytelephalangy, 9% had clubbed feet, 9% had premature rupture of membranes, and 9% had intraventricular hemorrhage detected through sonography or radiography. We also found 17 unique variants in ARSL for these 22 fetuses.Discussion: A previously unpublished association of ARSL variants with intrauterine fetal death or stillbirth has been noted in this study. It is also possible that intracranial hemorrhage is an underrecognized feature associated with CDPX1 variation. However, there have been challenges in applying ACMG criteria to ARSL, a gene without an associated Variant Curation Expert Panel.Conclusion: This literature review and case series highlights which features of CDPX1 manifest prenatally, as well as introduces new phenotypes that have not been previously identified.

Genetic counseling graduate students face growth and challenges across a variety of axes both personally and professionally throughout their training. The formation of leader‐led supervision groups for second‐year genetic counseling students has created a safe space for students to give and receive feedback, process their positionality in complex clinical scenarios and the medical system at large, dissect psychosocial counseling theory, and share personal and professional experiences with the overall aim of supporting their growth. This work requires faculty facilitators who are invested in student growth and operate from a framework of empathy, humanism, curiosity, and vulnerability. The authors share their reflections on stepping into the facilitator role with no prior experience other than their work in clinical genetic counseling in varied practice settings. Common themes across four cohorts of students are presented along with reflections on facilitator growth, consideration of student developmental stages, and the parallel process between providing clinical services to clients and educating students. The authors hope to highlight the value of processing cases, inspire other genetic counselors to engage in this work, and normalize the experiences of those already running genetic counseling student process groups.

Objective: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre‐ and postnatal phenotypes associated with GREB1L.Methods: We solicited cases from the Fetal Sequencing Consortium, screened a population‐based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes.Results: One hundred twenty‐seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot.Conclusion: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.